HIV-1 TAT-mediated microglial activation: role of mitochondrial dysfunction and defective mitophagy.

While the advent of combination antiretroviral therapy (cART) has dramatically increased the life expectancy of HIV-1 infected individuals, paradoxically, however, the prevalence of HIV-1-associated neurocognitive disorders is on the rise. Based on the premise that the cytotoxic HIV-1 protein, transactivator of transcription (TAT), a known activator of glial cells that is found to persist in the central nervous system (CNS) despite cART, we sought to explore the role of defective mitophagy in HIV-1 TAT-mediated microglial activation. Our results demonstrated that exposure of mouse primary microglia to HIV-1 TAT resulted in cellular activation involving altered mitochondrial membrane potential that was accompanied by accumulation of damaged mitochondria. Exposure of microglia to HIV-1 TAT resulted in increased expression of mitophagy signaling proteins, such as PINK1, PRKN, and DNM1L, with a concomitant increase in the formation of autophagosomes, as evidenced by increased expression of BECN1 and MAP1LC3B-II. Intriguingly, exposure of cells to HIV-1 TAT also resulted in increased expression of SQSTM1, signifying thereby a possible blockade of the mitophagy flux, leading, in turn, to the accumulation of mitophagosomes. Interestingly, HIV-1 TAT-mediated activation of microglia was associated with decreased rate of extracellular acidification and mitochondrial oxygen consumption and increased expression of proinflammatory cytokines, such as Tnf, Il1b, and Il6. HIV-1 TAT-mediated defective mitophagy leading to microglial activation was further validated in vivo in the brains of HIV-1 transgenic rats. In conclusion, HIV-1 TAT activates microglia by increasing mitochondrial damage via defective mitophagy. ABBREVIATIONS: 3-MA: 3-methyladenine; Δψm: mitochondrial membrane potential; ACTB: actin, beta; AIF1: allograft inflammatory factor 1; ATP: adenosine triphosphate; BAF: bafilomycin A